Apelin-13 as a novel diagnostic laboratory biomarker in thromboembolic disorders: a review of literature with prospective insights

Abstract

Thromboembolic disorders, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are major global health concerns, causing significant morbidity and mortality. Early diagnosis is crucial for effective treatment and improved patient outcomes. Recent research has identified Apelin-13, a bioactive peptide in the apelin family, as a promising diagnostic biomarker for Thromboembolic disorders. Apelin-13 supports vascular health by regulating protease balance through plasminogen activator inhibitors and modulating endothelial cell function. Additionally, it plays a vital role in coagulation, with elevated levels associated with an increased risk of clot formation, suggesting its utility in predicting thrombosis risk, particularly in preoperative evaluations. Findings indicate that the Apelin-13 pathway shows significant promise as a biomarker for Thromboembolic disorders, underscoring its potential therapeutic applications and the need for further investigation. This review synthesizes current literature on thromboembolic disorders and associated laboratory biomarkers, with a particular focus on Apelin-13. It examines Apelin-13’s role in disease mechanisms, its physiological functions, and its potential as a diagnostic biomarker in thromboembolic conditions.

Introduction

Thromboembolic (TE) disorders, which include deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, are major worldwide health problems because they have high rates of illness and death [1]. Prompt and precise diagnosis is essential for efficient management and treatment of many disorders. Nevertheless, existing diagnostic approaches frequently depend on a blend of clinical evaluations, imaging modalities, and recognized biomarkers, which may not consistently offer enough sensitivity or specificity. This has stimulated continuous investigation into innovative biomarkers that could augment diagnostic precision and better patient outcomes [2].

Recently, Apelin-13, as a biologically active peptide of the apelin family, has been considered an attractive biomarker in TE disorders [3]. The precise role of Apelin-13 in the development and diagnosis of TE disorders has yet to be completely understood despite its involvement in these important physiological processes [3,4,5].

This review examines the physiological role of Apelin-13 and its potential as a diagnostic biomarker for TE disorders. It reviews published studies to understand its function and efficacy, as well as its potential to enhance current diagnostic methodologies for treating TE conditions, complementing or improving existing treatments.

A short overview of thromboembolism disorders

The term “thromboembolism disorders” (TE) refers to a group of conditions characterized by the formation of blood clots, known as thrombi. These clots can obstruct blood vessels, leading to the occurrence of emboli, which happen when a clot travels through the circulatory system and lodges in a different location [6].

Venous thromboembolism (VTE) is a TE event that occurs in the venous system, which is divided into DVT and/or PE [7]. It is the third leading cause of vascular death after heart attack and stroke [8, 9]. The most concerning fact about this disorder is that 60% of VTE cases are hospital-acquired, making VTE the most common preventable cause of death in hospitalized patients [10, 11].

It seems that variable factors such as age, gender, race, and medical conditions have caused differences in the incidence of VTE in geographic regions [12].

The American Heart Association estimates the total number of VTE cases in the United States to be about 1,220,000 in 2021 [13]. Overall, the reported incidence of VTE in Europe and the United States is estimated to be about 1–2 per 1,000 people per year [14]. Among the US adult population, the lifetime risk of VTE is estimated to be 8% [15].

Thrombotic embolism is a dangerous disorder in which a thrombus develops, usually as a result of vascular damage, blood stasis, or hypercoagulability, and then breaks apart to move through the circulation as an embolus [16]. When an embolus becomes trapped in a smaller blood channel, it obstructs blood flow, causing tissue or organ damage from ischemia. The disorder comprises three primary processes: thrombus development, embolization, and vascular occlusion, and is regulated by conditions identified by Virchow’s triad [16, 17]. Timely diagnosis and understanding of these pathways are required for effective thrombotic embolism therapy to avoid serious consequences.

VTE leads to the formation of thrombi, which are structures rich in platelets, red blood cells, leukocytes, and fibrin, in almost all venous districts, especially in the valve pockets and dilated sinuses of the lower extremities [18]. The formation and release of thrombus, known as Virchow’s triad, includes blood flow stasis, hypercoagulability, disruption, and damage to endothelial function, which is an understandable way to represent the pathophysiology of VTE [19]. When the mentioned factors are present, the coagulation cascade, which is the series of enzymatic reactions, is activated, which initially leads to the formation of fibrin and the stabilization of platelets, leading to the growth and expansion of the thrombus and finally obstruct the blood flow [20, 21].

VTE is often multifactorial, And the risk factors are conditions and behaviors that increase the possibility of blood clot formation and cause disruption of blood flow and movement and blockage of blood vessels. Traditional risk factors for VTE include conditions of immobility and prolonged inactivity, such as long-haul flights [22, 23], hospitalization [24], recent surgeries, especially knee and arthroplasty and abdominal and hip surgeries [25, 26], trauma, and fractures which cause restriction in movement [27,28,29], male sex [30], old age [31], obesity [32, 33], smoking [34], family history, and genetic conditions that affect blood clotting, such as Factor V Leiden (FVL) mutation [35], Prothrombin G20210A Gene Mutation (PGM) [36], and Plasminogen Activator Inhibitor-1 [37].

Also, disorders and diseases that cause hypercoagulability, including diabetes [38], cancer [39], antiphospholipid syndrome [40, 41], use of Oral Contraceptives and Hormonal Replacement [42, 43], pregnancy, thrombophilic disorders, chronic kidney disease, autoimmune disorders [44, 45], sickle cell anemia [46], and infection, including with viruses such as SARS-CoV-2 [47].

Thromboinflammation

Thromboinflammation is a complex process that involves the bidirectional relationship between thrombosis (blood clotting) and inflammation processes. In this state, inflammatory responses can trigger thrombosis, while thrombotic events can further exacerbate inflammation [48]. This vicious cycle can lead to severe complications in various diseases, including cardiovascular conditions and COVID-19 [49, 50].

Thromboinflammatory biomarkers play a pivotal role in the interplay between inflammation and thrombosis, with key contributors including Tissue Factor (TF), Plasminogen Activator Inhibitor-1 (PAI-1), Tumor Necrosis Factor-alpha (TNF-α), interleukins (IL-6, IL-1β), Angiopoietin, adhesion molecules (VCAM1, ICAM), and complement components (C3b, C5a) [51, 52].

TF initiates coagulation and is linked to hypercoagulable states such as those observed in severe COVID-19, while elevated PAI-1 impairs fibrinolysis [50], fostering thrombosis in conditions like Idiopathic Multicentric Castleman Disease (iMCD) [53]. TNF-α and interleukins drive pro-inflammatory and prothrombotic responses [54], while markers like Angiopoietin, VCAM1, and ICAM reflect endothelial activation. Complement system components amplify thromboinflammation, highlighting the interconnected roles of these biomarkers in vascular pathology [53].

Recognizing the role of thromboinflammation and its biomarkers is crucial in clinical care. Elevated levels of these markers can aid in diagnosing patients at higher risk of developing blood clots, while also providing insights into disease severity and potential outcomes, especially in conditions like stroke and COVID-19 [55]. This understanding opens doors to targeted treatments, such as using statins to lower platelet cholesterol and tissue factor activity, offering promising new approaches to managing thromboinflammatory conditions [56].

Diagnostic biomarkers in TE

Although an optimal and clear strategy for the diagnosis of TE has not been determined, several new biomarkers for the diagnosis of TE have been identified and used in recent years, and more are under active investigation, ultimately leading to significant progress in the diagnosis of TE [57, 58]. A combination of biomarkers with the Wells score [59], can increase the diagnostic accuracy of TE in patients and guide decisions about further diagnostic interventions.

Some of the biomarkers utilized in the diagnosis of TE include D-dimer, P-selectin, and fibrin degradation products (FDP) [58, 60, 61]. These biomarkers, together with clinical history, physical examination, and imaging modalities, can aid in the diagnosis and monitoring of TE events.

D-dimer

D-dimer molecules are produced when cross-linked fibrin is broken down in the context of fibrinolysis [62, 63]. D-dimer measurement, along with clinical decision rules (CDRs), such as the Wells criteria [64], and the Geneva score [65], are valid and practical methods for the roll-out of VTE in patients [66, 67]. The Wells criteria and Revised Geneva score are clinical tools used to assess the probability of DVT or PE. They guide diagnostic testing and resource utilization, often combined with D-dimer testing and clinical judgment, to evaluate patients with suspected PE [68, 69]. D-dimer is generally a test with high sensitivity but low specificity. Many conditions lead to elevated D-dimer levels, including pregnancy, infection, malignancy, and post-surgical conditions [70, 71]. Also, even partial activation of the coagulation cascade involves increased fibrinolysis, resulting in elevated D-dimer levels [72], and thus can cause false-positive D-dimer results [62].

D-dimer testing may be contraindicated in certain conditions, such as when there is a high pre-test chance of PE or DVT and imaging is necessary regardless of the test result. Furthermore, situations such as pregnancy and cancer can boost D-dimer levels on their own, potentially leading to false results if utilized without further diagnostic procedures [73].

Serum Profılın-1

Serum Profilin-1’s role in regulating the actin cytoskeleton and platelet function makes it a possible biomarker in TE disorders. Profilin-1 regulates actin polymerisation, which is an important component of platelet activation and aggregation, and hence plays a role in cellular processes that influence thrombogenesis [74]. Profilin-1 overexpression may enhance platelet reactivity and help in the formation of blood clots. Hence, greater protein serum levels have been associated with an increased risk of thrombosis. Profilin-1 has the potential to serve as a marker of endothelial dysfunction and vascular injury. These two elements are critical for the development of TE events such as PE and DVT. Profilin-1 may be useful in the management, risk assessment, and early detection of TE diseases [74,75,76,77].

A recent study evaluated the utility of serum Profilin-1 as a diagnostic and prognostic biomarker for PE. Among 102 PTE patients and 64 healthy controls, Profilin-1 levels were significantly higher in PE patients (median 2878 pg/mL vs. 579 pg/mL, p < 0.001), with a diagnostic sensitivity and specificity of 76.47% and 79.69%, respectively. Higher Profilin-1 levels were also associated with mortality, showing 90.91% sensitivity and 71.25% specificity for prognosis at levels ≥ 3292.1 pg/mL. The study findings suggest that Profilin-1 is a promising biomarker for PE diagnosis and prognosis [75].

Troponin

Troponin, primarily known as a cardiac biomarker for diagnosing myocardial infarction (MI), may also increase in TE conditions like DVT and PE [78]. Elevated troponin levels in PE are a result of right heart strain caused by increased pulmonary artery pressure. These elevated levels can help assess the severity of the embolism, as they are associated with right ventricular dysfunction. Higher troponin levels in PE patients are linked to worse clinical outcomes and increased mortality risk, making troponin a valuable prognostic biomarker for identifying high-risk patients and guiding therapeutic decisions [78, 79]. While troponin’s role in PE prognostication shares some similarities with its use in cardiac events, understanding the nuances in its elevation patterns, magnitude, and clinical context is crucial for accurate interpretation and optimal patient management [80, 81]. Clinicians must consider the possibility of PE in patients with elevated troponin, especially when the clinical picture is not typical for acute coronary syndrome.

Soluble P-selectin

P-selectin is an adhesion glycoprotein found in the α-granule of platelets and the Weibel-Palade body of the endothelium. Cell surface P-selectin helps leukocytes adhere to the thrombus, and platelet P-selectin helps to bind more leukocytes and propagate venous thrombosis [82, 83]. Studies support the possible involvement of P-selectin in the pathogenesis of TE [60, 84, 85]. In conclusion, it has been proposed as a biomarker with a diagnostic function for VTE. This biomarker, when combined with a Wells score ≥ 2, soluble P-sel > 90 ng/ml has shown a positive predictive value of 100% [86, 87].

Factor V Leiden

The Factor V Leiden mutation is a genetic variation that results in a mutant Factor V protein that is resistant to deactivation by activated protein C, increasing the likelihood of blood clot formation. This mutation significantly raises the risk of developing TE illnesses such as DVT and PE [88, 89]. Genetic testing can detect Factor V Leiden, a biomarker that allows for the early detection of persons who are prone to clotting difficulties. This information is crucial for risk classification and guiding preventive measures in individuals at high risk of TE events [88, 90].

FDP (fibrin degradation products)

Fibrin Degradation Products (FDP) are biomarkers that reflect the breakdown of fibrin, a crucial component of blood clots, and are, therefore, strongly linked to ET illnesses [61, 91]. Elevated FDP levels indicate enhanced fibrinolytic activity, which happens when the body attempts to remove blood clots and is important in detecting disorders such as DVT and PE [92]. High FDP levels indicate continuous clot production and breakdown, implying active TE processes. Clinically, FDP testing helps to diagnose and monitor the severity of TE episodes, as well as guide treatment approaches such as anticoagulant medication [92]. Some studies have shown that FDP is involved in the development and progression of atherosclerosis and thrombosis [93, 94].

Apelin family and its subtypes

The apelin family is a set of peptides synthesized from the apelin gene that plays an important role in a variety of physiological and pathological processes [95]. These peptides work as endogenous ligands for the apelin receptor (APLNR or APJ), a G protein-coupled receptor implicated in cardiovascular function, metabolism, and homeostasis [96].

Apelin peptides are derived from a 77-amino acid precursor known as preproapelin, which is processed into multiple bioactive isoforms of varying length [97]. These include Apelin-36, the longest active form; Apelin-17, a shorter and more powerful fragment; and Apelin-13, which has been intensively examined because of its great stability and activity. Additionally, [Pyr1]-Apelin-13, a pyroglutamated version of Apelin-13, has increased bioactivity and resistance to enzymatic degradation [97, 98].

Apelin is a natural ligand for the G protein-coupled receptor APJ, so the name apelin comes from the APJ Endogenous Ligand. The apelin/APJ system is widely distributed in vivo. The gene encoding Aplin (APLN), which encodes a 77 amino acid propeptide, is located on chromosome Xq25-26.1 [97]. Preproapelin is cleaved from its C-terminus to produce a mature apelin peptide (apelin-36,−17,−12, and − 13), the latter of which also exists as a pyroglutamyl form, [Pyr1]apelin-13 [99]. Each group of subtypes has a different activity, and shorter subtypes lead to the activation of the APJ receptor more effectively; because of this, the activity of Apelin-13 and Apelin-17 is much stronger than that of Apelin-36, and the different binding affinities for their receptor determine the different APJ signaling pathways activated in cells [100, 101].

Apelin-13 and its physiological function

Apelin-13, the most biologically active isoform of the apelin family, is an endogenous peptide derived from the apelin gene (APLN). Among all apelin subtypes, Apelin-13 has the highest affinity for the Apelin receptor (APJ), a G protein-coupled receptor, through which it regulates various physiological processes in the body. Its biological significance makes it a key player in pathways involving cardiovascular function, fluid homeostasis, and energy metabolism [102,103,104,105].

Apelin-13 plays a diverse role in physiological processes, including reducing inflammation in cardiovascular and metabolic diseases [106], promoting vasodilation, regulating blood pressure, and enhancing heart function [107], making it a promising therapeutic target for conditions such as heart failure, hypertension, and metabolic disorders [108]. It supports angiogenesis, aiding tissue repair and growth [105], and improves insulin sensitivity while regulating glucose and lipid metabolism, contributing to obesity and diabetes management [104]. Apelin-13 also helps maintain fluid balance by influencing water and electrolyte levels, impacting blood volume and kidney function [109]. Additionally, it has roles in the central nervous system, including neuroprotection, appetite regulation, and stress response [110], as well as in reproductive processes like ovulation and placental development [104].

Apelin-13 is an important regulator of endothelial cell activity and vascular health. It has a wide range of actions on endothelial cells, contributing to a variety of physiological and pathological conditions [111]. Apelin-13 has been demonstrated to protect endothelium cells, especially when they are injured or under stress. Apelin-13 inhibits hydrogen peroxide-induced cell death in endothelial cells by lowering intracellular reactive oxygen species (ROS) levels. This protective effect implies that Apelin-13 may aid to preserve endothelium integrity in the face of oxidative stress [112, 113].

Most studies agree that apelin/APJ’s action on the cardiovascular system is due to its similarity to that of the angiotensin receptor. In the cardiovascular system, Apelin-13 leads to a decrease in blood pressure and modulates the contraction of heart tissue and blood vessels [114,115,116]. Also, about the effect of Apelin-13 on changes in blood pressure and heart rate studies have been conducted, and a decrease in blood pressure and an increase in heart rate have been reported [117, 118].

Apelin-13 can protect the heart against ischemic damage and reperfusion both in vivo and in vitro. this effect is associated with inhibiting apoptosis and ferroptosis and stimulating autophagy. Apelins also protect the heart from ischemic damage and reperfusion [119]. Also, in 2016, an in vitro study showed that Apelin-13 treatment may reduce myocardial fibrosis caused by myocardial infarction, and this cardioprotective effect may be mediated through the regulation of NF-κB signaling [120].

Apelin-13 plays a multifaceted role in vascular and organ health, influencing endothelial function and offering therapeutic potential. It promotes vasodilation in well-managed chronic kidney disease patients and may enhance the body’s natural ability to break down clots [121]. In vitro studies suggest that Apelin-13 can reverse endothelial-to-mesenchymal transition (EndMT) and associated kidney fibrosis, offering renoprotective benefits by suppressing the TGFβ/Smad/CEBPA pathway [122]. However, Apelin-13 also increases MLC phosphorylation in vascular smooth muscle cells, leading to vasoconstriction and potentially worsening hypertension when the endothelium is damaged by ADMA [123]. Additionally, it has been shown to reduce pulmonary vascular permeability in mice with acute lung injury, likely through AMPK activation to improve mitochondrial function and autophagy [124]. These findings emphasize Apelin-13 as a complicated vascular regulator.

Figure 1 represents the physiological function of Apelin in the human body, and Table 1 presents animal studies investigating its physiological role.

Fig. 1

The main physiological functions of Apelin-13. Key physiological functions of Apelin-13: (1) Anti-inflammatory effects in cardiovascular and metabolic diseases, (2) cardiovascular health via vasodilation, blood pressure regulation, and heart function improvement, (3) promotion of angiogenesis for tissue repair, (4) regulation of metabolism, improving insulin sensitivity and glucose-lipid balance, (5) fluid balance control affecting blood volume and kidney function, (6) neuroprotective roles in the central nervous system, including appetite and stress regulation, and (7) contributions to reproductive processes like ovulation and placental development

Table 1 Animal studies investigating the physiological role of Apelin-13

Cellular-Molecular mechanism of Apelin-13 in thrombosis

Apelin-13 is also involved in the regulation of various physiopathological mechanisms such as apoptosis, inflammation, angiogenesis, oxidative stress, and energy metabolism [133].

In CVDs, Apelin shields the heart by curbing fibrosis, obstructing hypertrophy and clotting, boosting contractility, and alleviating inflammation and oxidative stress. It not only shrinks infarction size but also fosters revascularization post-myocardial infarction (MI). Nonetheless, cardiovascular ailments coincide with diminished apelin and heightened Angiotensin-Converting Enzyme 2 (ACE2) levels in the bloodstream [134].

In an animal study, the Apelin-deficient mice exhibited advanced heart failure (HF) and demonstrated diminished tail-bleeding time alongside heightened thrombus formation, a condition that intravenous Apelin-13 administration can facilitate [135]. This in vivo experiment cannot rule out the possibility that plasma apelin or apelin from ECs near thrombosis may be involved in platelet function, but in vitro, apelin inhibits Ca2 + mobilization mediated by collagen and thrombin receptor activation. Additionally, the APJ is expressed on the outer membrane of resting human platelets, and when platelets become active, the APJ is released with platelet-derived microparticles [136]. The depressed aggregation that apelin caused can be offset by L-NAME, suggesting that apelin’s antithrombotic effects are mediated by platelet-derived nitric oxide (NO). The research on the antithrombotic effect of apelin has just started, but it undoubtedly provides a new avenue for the regulatory role of apelin in the cardiovascular system [134].

In vascular diseases, the apelin pathway enhances NO levels, reduces reactive oxygen species (ROS) production, and mitigates the RAS system by promoting ACE2 expression and inhibiting AT1R signaling through APJ heterodimerization. ACE2 functions in a feedback loop to cleave apelin peptides while converting Ang II into vasoprotective Ang (1–7) via the RAS system. This pathway promotes angiogenesis, restores endothelial integrity, and inhibits platelet activation [137, 138]. ACE2 degrades not only native apelin peptides but also other peptidases, including NEP and KLKB1. Consequently, metabolically stable apelin analogs and non-peptide APJ agonists are proposed as alternatives to regulate the apelin pathway in vascular diseases [134].

Recent research indicates that Apelin-13 inhibits foam cell formation in cultured cells through the PI3K/Beclin-1 autophagic pathway [139]. Apelin mitigates TAC-induced aortic adventitial remodeling and fibrosis by suppressing miRNA122/CTGF/NFAT5 and LGR4/β-catenin signaling pathways [140]. Apelin mitigates obesity from diet by improving vascular integrity, and statins exhibit atheroprotective properties by activating the apelin/APJ pathway [141, 142]. It is significant to note that apelin inhibits platelet activation induced by thrombin and collagen, functioning as a robust antithrombotic agent [135]. Thus, it protects against thrombotic events.

The Apelin mechanism in preeclampsia operates by enhancing hemodynamic parameters and promoting angiogenesis while concurrently reducing ROS, proteinuria, and both renal and hepatic injury [105, 143]. Apelin increases insulin sensitivity, endothelial NO synthase (eNOS), AMPK, and Akt in insulin resistance. It also reduces inflammatory markers, adiposity, and glucose levels [144]. The mechanism of apelin in kidney disease operates through enhancing Akt/eNOS, renal perfusion, and catalase levels while concurrently diminishing apoptosis, TGF-ẞ, inflammation, and oxidative stress [121]. The apelin pathway in pulmonary arterial hypertension (PAH) operates by enhancing the levels of eNOS, BMPR2, and miR-424/503 while simultaneously reducing the proliferation and migration of pulmonary artery smooth muscle cells (PASMC) and fibroblasts, as well as alleviating right ventricular overload [145, 146]. The Apelin mechanism in erectile dysfunction operates by augmenting intracranial pressure, phosphorylated eNOS, and matrix metalloproteinase (MMP) activity while concurrently diminishing ROS, apoptosis, penile fibrosis, and the differentiation of fibroblasts [147]. In the aforementioned pathological states, the enhancement of the apelin pathway—achieved through the administration of native apelin peptides, apelin analogs, or non-peptide APJ agonists facilitates an increase in eNOS-mediated NO production, mitigates oxidative stress, decreases the secretion of inflammatory mediators, protects against apoptosis, and inhibits pathological remodeling.

In summary, it can be stated that Apelin exhibits a significant antagonistic effect on the action of vasoconstrictors, a phenomenon which is achieved through the inhibition of the formation and activity of reactive oxygen species, while simultaneously promoting the enhanced synthesis of NO, a vital signaling molecule in the vascular system [148, 149].

Figure 2 represents the biochemical pathways of how apelin acts.

Fig. 2

Cellular and molecular mechanisms of Apelin action in cardiovascular and vascular diseases. Apelin enhances ACE2 expression and inhibits AT1R signaling, reducing reactive oxygen species (ROS) production. This promotes the conversion of Ang II to Ang (1–7), a cardio-protective factor that stimulates nitric oxide (NO) production via eNOS and the MasR pathway. These processes lead to blood vessel dilation, angiogenesis, and prevention of vascular occlusion

Apelin-13: a novel diagnostic biomarker in TE

Studies have shown that serum levels of Apelin-13 are elevated in individuals with thromboembolism, suggesting its involvement in the prothrombotic cascade and potential use as a diagnostic biomarker for this condition [5, 150, 151].

In recent studies, the sensitivity and specificity of Apelin-13 as a biomarker for diagnosing TE diseases have been considered. The cutoff point for Apelin-13 in diagnosing TE disorders can vary depending on the study and the population being examined. However, many studies aim to identify a threshold concentration that provides the best balance between sensitivity and specificity for diagnosing conditions like VTE or PE [5, 152].

Apelin-13 levels in serum can be measured using various methods, with enzyme-linked immunosorbent assay (ELISA) being the most widely used due to its balance of specificity, sensitivity, and ease of use. Radioimmunoassay (RIA) is another immunoassay option, though it is less commonly employed. For highly precise and specific measurements, liquid chromatography-mass spectrometry (LC-MS) is a powerful alternative, offering exceptional accuracy for Apelin-13 quantification [77, 153]. Accurate measurement of Apelin-13 in serum requires careful consideration of several factors. Proper sample handling, including collection, storage, and processing, is essential to prevent degradation. The analytical method must have high specificity to distinguish Apelin-13 from other apelin isoforms and sufficient sensitivity to detect physiologically relevant concentrations. Standardization using appropriate standards and quality controls is crucial for reliable quantification. Additionally, pre-analytical variables such as fasting status, time of day, and other physiological factors should be accounted for in the study design to ensure accurate and consistent results [77, 153].

Apelin-13 demonstrated superior sensitivity and specificity in comparison to D-dimer, indicating its prospective role as a novel diagnostic biomarker for PE. Additional investigations within this domain are imperative to validate these results and to explore the clinical applicability of Apelin-13 as a diagnostic instrument for PE. Apelin-13 has the potential to facilitate earlier diagnosis and prompt initiation of therapeutic interventions in affected individuals across various age demographics and genders [5]. In the investigation conducted by Kartas et al., the optimal cut-off value for Apelin-13 in both the patient and control cohorts was determined to be 1579 ng/ml through the utilization of receiver operating characteristic (ROC) curve analysis. The sensitivity of the assay was recorded at 92.7%, while the specificity was noted to be 96.7%. This investigation elucidated that the concentration of Apelin-13 in serum may serve as a novel diagnostic biomarker for individuals afflicted with PTE [151].

Recent studies have shown that serum levels of Apelin-13 are associated with adverse outcomes in patients with reduced ejection fraction HF and may be useful biomarkers in determining the prognosis of these patients [154, 155]. Also, preclinical and clinical studies have shown that disturbances in the Aplin pathway, contribute to the development and pathophysiology of diseases, especially CVDs [156, 157].

Considering the aforementioned roles of apelin, current developments in this field also focus on harnessing its therapeutical potential. Applications in a broad array of disorders, such as preeclampsia [105, 143], insulin sensitivity [158], insulin resistance [144], atherosclerosis [156, 159], aortic aneurysms [160], MI, HF [156], kidney disease [121], PAH [145], and ED [147], have been explored with promising results.

In a recent study, 52 participants suspected of PE were examined. Findings from CT angiography classified participants into two groups: those with PE and those without. The serum D-dimer and Apelin-13 biomarkers were then analyzed and compared between the groups. The researchers concluded that Apelin-13 serum levels may act as a novel diagnostic biomarker for PE [5].

Also, in another recent research, 124 individuals were examined, comprising 94 PE cases and 30 healthy controls. PE was identified using chest computed tomography angiography. Post-diagnosis, Apelin-13 levels were assessed via enzyme-linked immunosorbent assay (ELISA). The study revealed no significant variance in Apelin-13 levels between patient and control groups or among death risk categories, indicating it is not a reliable biomarker for PE diagnosis [150].

In a separate investigation conducted in recent years, 53 patients with PE and 35 healthy controls were examined. The control group comprised healthy volunteers undergoing routine health checks. The serum levels of Apelin-13 were measured in both groups, followed by a comparative analysis. The researchers found significantly higher Apelin-13 levels in PE patients. These results suggested that apelin may be a valuable biomarker and therapeutic target for acute PE in future research [152].

In another study, 142 patients were analyzed, comprising 82 with PE and 60 controls. Serum Apelin-13 levels were assessed via venous blood samples using an ELISA kit. The findings indicate that serum Apelin-13 may serve as a novel diagnostic biomarker for PTE. Additionally, Apelin-13 levels were elevated in patients with DVT. These findings imply the potential use of Apelin-13 as a biomarker for acute PTE and DVT in future research [151].

Some biomarkers can be used to diagnose patients with TE, such as D-dimer, BNP, troponin, etc., but due to the widespread use of D-dimer, in most studies, this biomarker has been compared with Apelin-13 [5, 150, 152].

The quantity of serological biomarkers employed in the identification of PTE remains limited. D-dimer represents a non-invasive biomarker frequently utilized for the diagnosis of PTE, indicating the presence of endogenous fibrinolytic activation [161]. The sensitivity of D-dimer exhibits a considerable degree, whereas its specificity remains relatively low [162, 163]. Recent research indicates that Apelin-13 demonstrates superior sensitivity and specificity in patient diagnosis, suggesting its potential as an effective, novel biomarker [5, 151].

Table 2 presents a summary of human studies investigating the role of Apelin-13 as a biomarker for TE conditions.

Table 2 Diagnostic biomarker studies of Apelin-13 in thromboembolic disorders

Table 2. Diagnostic biomarker studies of Apelin-13 in TE.

Challenges and limitations

There exist multiple constraining variables. The investigators contend that investigations encompassing more extensive patient cohorts will unequivocally elucidate the correlation between PTE and Apelin-13. These findings, along with the significance of Apelin-13, are anticipated to enhance clinical methodologies in the future diagnosis of PE [151]. Research related to the relationship of Apelin-13 with TE disorders is limited; many of them are the first time to deal with this issue in different dimensions.

Prudence must be employed when interpreting plasma concentrations of apelin, particularly in individuals exhibiting diminished glomerular filtration rate (GFR), as the elimination of numerous peptides is influenced, and an elevation in arginine vasopressin (AVP) may intrinsically lead to a reduction in apelin levels [134].

The sample population size that was analyzed in this investigation was rather restricted. This limitation may elucidate the absence of statistically significant differences in serum Apelin-13 levels between the cohort of patients who survived and the subgroup of those who did not survive within the entire population. Nevertheless, the researchers contend that the constrained size of the study does not appear to affect the fundamental observations derived from the research detrimentally [165].

The abbreviated half-life of native apelin peptides, approximately 5 min, is attributable to swift proteolytic degradation facilitated by specific peptidases [166, 167], including ACE2 [118], plasma kallikrein (KLKB1) [168], and neprilysin (NEP) [169]. This phenomenon, in conjunction with the desensitization of the APJ [170], significantly limits the translational potential of this biological system, thereby necessitating an investigation into apelin analogs that exhibit resistance to endogenous degradation, as well as the development of non-peptide receptor agonists that demonstrate enhanced efficacy [134].

Conclusion and future directions

Table 3 represents a summary of the role, mechanism of action, diagnostic potential, challenge, and clinical application of Apelin-13.

Table 3 Summarize of Apelin-13

Apelin-13 is a peptide involved in cardiovascular and metabolic regulation. Due to its multifaceted role in vascular biology and disease pathology, it holds promise as a modern diagnostic laboratory potential biomarker for TE disorders, including PE, DVT, stroke, etc [107, 171]. Its ability to modulate endothelial function, inhibit platelet aggregation, and influence the coagulation cascade positions it as a valuable tool for early diagnosis, risk assessment, and monitoring of thrombotic diseases. Its combination with other markers like D-dimer could enhance diagnostic precision, making it a valuable tool in clinical practice [5].

Exploring the potential of combining Apelin-13 with additional biomarkers may improve diagnostic accuracy for conditions such as PE, DVT, and other TE diseases. While Apelin-13 shows promise as a diagnostic tool, additional research is essential to fully understand its mechanisms and validate its application in a wide range of clinical settings and diverse populations.

To establish its diagnostic and prognostic value in clinical practice, further clinical research and validation studies are necessary to clarify findings and evaluate their clinical significance. Future investigations should focus on larger sample sizes and diverse populations to compare its specificity and sensitivity with traditional markers like D-dimer.